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DEVELOPMENT OF AN ER-POSITIVE BREAST CANCER METASTASIS MODEL THROUGH STROMAL-EPITHELIAL INTERACTIONS
Background: Breast cancer metastasis kills more than 40,000 American women each year. Sixty - 80% of these metastases retain estrogen receptors (ER) and progesterone receptors (PR) and are hormone dependent. Nevertheless, the influence of estrogens and progesterone on breast cancer metastasis remains largely unknown, because of the unavailability of appropriate models. It is the major goal of this proposal to develop an ER+ metastasis model. The stromal compartment plays an important role in the growth and aggressiveness of adenocarcinomas. Fibroblasts obtained from tumor stroma (called "reactive" stroma) have different expression profiles when compared to their normal counterparts and increase the aggressiveness of epithelial breast cancer cells by increasing proliferation rates and invasiveness. In preliminary studies, we have generated a "reactive" mouse mammary stromal cell line called BJ3Z. We have also developed a model of ER+ MCF-7 human breast cancer lymph node metastasis in nude mice. In the present studies we will combine MCF-7 cells with BJ3Z cells to generate an ER+ solid tumor metastasis model. Hypothesis: We propose that mixing ER+ malignant breast epithelium with "reactive" stroma will generate an estrogen-dependent solid tumor with enhanced metastatic potential. We propose that "reactive" stroma increases the proliferation rate and metastatic potential of ER+ breast cancer cells by inducing specific genetic changes at the orthothopic site (mammary gland). This increases the ability of tumor cells to metastasize. Specific aims: Aim 1. To characterize in vitro, the influence of BJ3Z cells on estrogen dependent growth and aggressiveness of ER+ MCF-7 human breast cancer cells. Aim 2. To generate solid tumor models in nude mice of ER+ MCF-7 cells mixed with BJ3Z, use fluorescent tracking methods to define tumor growth and metastasis, and study the hormone dependence of this process. Aim 3. To identify genes altered by the presence of "reactive" stroma in solid MCF-7 tumors. Study design: Three cell lines will be used: (1) ER+ MCF-7 human breast cancer cells; (2) a mouse mammary gland-derived "reactive" stroma cell line, BJ3Z; and (3) normal mammary fibroblast controls. Cells will be used for in vitro co-culture experiments evaluating proliferation and invasive potential of MCF-7 cells. In vivo, green fluorescent MCF-7 cells will be mixed with red fluorescent BJ3Z or normal fibroblast controls, and injected into mammary glands of nude mice. The role of estradiol on tumor growth and metastatic spread will be assessed. Solid tumors will be used for laser capture and expression profiling studies. Potential outcomes: Development of an ER+ model of breast cancer metastasis will be a unique tool to study hormonal influence in this process, and to identify participating genes. This will provide interesting targets to interfere with metastasis of ER+ breast cancers; the most common type.
Breast cancer metastasis kills more than 40,000 American women each year. The majority of primary cancers and their metastases contain receptors for estrogens (ER) and progesterone (PR) and are hormone dependent. Despite this, the contribution of hormones to breast cancer metastasis is unknown because appropriate models do not exist. The aim of this study is to create ER+ models of breast cancer metastasis. All organs in the body are composed of two cell layers: the epithelium and the stroma. Epithelial cells cover the surface of an organ and are the sites of most cancers. The stroma surrounds the epithelium, providing support for epithelial cell survival. In the stroma, the main cell type is the fibroblast. Fibroblasts extracted from tumor stroma - called "reactive" stroma - increase the aggressiveness and metastatic potential of breast cancer cells. We have developed a new "reactive" stroma cell line called BJ3Z. I hypothesize that co-injection of ER+ human breast cancer cells with BJ3Z cells in mammary glands of mice will increase metastasis of the ER+ tumor cells to distant organs. I will use this solid tumor model to study the effects of estrogens and progestins on metastasis. Additionally, in solid tumors, I will identify genes in the ER+ human breast cancer cells that are altered by proximity to ?reactive? stroma. Development of an in vivo ER+ human breast cancer metastasis model will help to understand the influence of estrogens and progestins (routinely used for hormone replacement therapy worldwide) in the metastatic process. Identification of genes involved in this process could provide powerful targets to block metastasis of ER+ breast cancers; the most common type of metastases.